Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
J Pineal Res. 2013 Sep;55(2):184-94. doi: 10.1111/jpi.12061. Epub 2013 May 25.
Chemoresistance in hepatocellular carcinoma (HCC) is associated with multiple cellular responses to environmental stresses, such as nutrient deprivation and hypoxia. Nevertheless, whether ER stress resulting from nutrient deprivation and tumor hypoxia contributes to drug resistance remains unclear. Melatonin increased the efficacy of chemotherapeutic drugs in hepatocellular carcinoma in our previous studies. However, the effects of melatonin on endoplasmic reticulum (ER) stress-induced resistance to chemotherapeutic agents in HCC have not been tested. The effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells against doxorubicin was investigated in this study. Pretreatment of HepG2 and SMMC-7721 cells (two human hepatocellular carcinoma cell lines) with tunicamycin, an ER stress inducer, drastically decreased the rate of apoptosis generated by doxorubicin. Interestingly, co-pretreatment with tunicamycin and melatonin significantly increased apoptosis induced by doxorubicin. Simultaneously, the expression of phosphorylated AKT (p-AKT) was elevated in HepG2 and SMMC-7721 cells given tunicamycin but reduced in the presence of melatonin. Furthermore, consistent with inhibition of AKT activation by using the PI3K inhibitor LY294002, melatonin elevated the levels of CHOP (C/EBP-homologous protein) and reduced the levels of Survivin (a member of the inhibitor of apoptosis protein family)suggesting that inhibition of the PI3K/AKT pathway by melatonin-reversed ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells. These results demonstrate that melatonin attenuates ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by down-regulating the PI3K/AKT pathway, increasing the levels of CHOP and decreasing the levels of Survivin.
肝癌（HCC）的化学耐药性与细胞对环境应激（如营养缺乏和缺氧）的多种反应有关。然而，营养缺乏和肿瘤缺氧引起的内质网（ER）应激是否导致药物耐药性尚不清楚。在我们之前的研究中，褪黑素增加了化疗药物在肝癌中的疗效。然而，褪黑素对肝癌细胞中内质网（ER）应激诱导的化疗药物耐药性的影响尚未得到测试。本研究旨在研究人肝癌细胞抵抗阿霉素时 ER 应激反应的作用。用 ER 应激诱导剂衣霉素预处理 HepG2 和 SMMC-7721 细胞（两种人肝癌细胞系），可显著降低阿霉素诱导的细胞凋亡率。有趣的是，衣霉素和褪黑素的共同预处理显著增加了阿霉素诱导的细胞凋亡。同时，在给予衣霉素的 HepG2 和 SMMC-7721 细胞中，磷酸化 AKT（p-AKT）的表达升高，而在存在褪黑素的情况下则降低。此外，与使用 PI3K 抑制剂 LY294002 抑制 AKT 激活一致，褪黑素升高 CHOP（C/EBP 同源蛋白）的水平并降低 Survivin（凋亡抑制蛋白家族的一员）的水平，提示褪黑素通过抑制 PI3K/AKT 通路逆转 ER 应激诱导的人肝癌细胞对阿霉素的耐药性。这些结果表明，褪黑素通过下调 PI3K/AKT 通路，增加 CHOP 的水平并降低 Survivin 的水平，减轻内质网应激诱导的人肝癌细胞对阿霉素的耐药性。
